Pulmonary hypertension is a critical determinant of morbidity and mortality in various pediatric diseases. Despite advances in therapies, long-term outcomes in many settings remain poor. Although reasons for this are multi-factorial, one critical component is the relative lack of disease-defining knowledge regarding the functional impact of the disease on the right heart and coupled pulmonary vasculature. In fact, clinically, pulmonary arterial hypertension continues to be evaluated predominantly as a distal vascular phenomenon, and only limited recognition is given to the fact that the pulmonary arterial system (PA) is intimately coupled with right ventricular function in health and disease. Functionally speaking, RV-PA coupling is driven by the principles of hydrodynamic and mechanical energy transfer and is thus not markedly dependent on the biological heterogeneity of the pediatric PH population. Over the last 7 years, our group using a reverse bedside-to-bench approach have developed novel markers of RV afterload using vascular input impedance principles, and have shown on studies of over 250 pediatric subjects with pulmonary hypertension that PVR does not represent the sole metric of RV afterload, that PA stiffness increases dramatically in pediatric pulmonary hypertension patients and consequently loads the RV to a proportionally greater level, and that inclusion of impedance and PA stiffness measures improves prediction of 1-year outcomes. These clinical studies generated a series of mechanistic studies to understand how the upstream pulmonary vessels stiffen, which have led to novel and interesting hypotheses regarding the role of extracellular matrix proteins in upstream vascular remodeling, mechanisms of healthy versus maladaptive remodeling, and differences in the developing versus the fully developed RV-PA system. These are currently being tested by our group and others through parallel efforts. This K24 project proposes a unique combination of research studies and training efforts to advance clinical evaluation of PH while training clinical research fellows with both sold fundamental understanding of underlying physics and hemodynamics and accurate application of such principles to novel clinical diagnostics.